1. Field of the Invention
This invention relates to a polyethylene glycol with low ethylene glycol and diethylene glycol contents which is to be used in fields with application to a living body such as the pharmaceutical field and the cosmetic industry, and a process for producing the same.
2. Description of the Related Art
Polyethylene oxide, which is a material generally obtained by polymerizing ethylene oxide, has inherent characteristics of being viscous, causing no irritation, being soluble in water and having lubricating properties. Owing to these characteristics, this compound has been widely used in water base paints, paper coatings, adhesives, printing inks, surfactants and the like.
Among all, polyethylene glycol serves as an important material in producing drugs and cosmetics in the fields with respect to a living body such as the pharmaceutical field and the cosmetic industry, since it has excellent solubility and compatibility. In particular, polyethylene glycol compounds called xe2x80x9cMacrogolsxe2x80x9d having different molecular weights are listed as official drugs in the Pharmacopoeia of Japan and employed as dissolution aids and fillers in various drugs and cosmetic materials.
Polyethylene glycol contains ethylene glycol and diethylene glycol the contents of which are specified to 0.25% (2,500 ppm) or less in the United States Pharmacopoeia etc., with respect to polyethylene glycols having a molecular weight of 1,000 or less for use in fields with application to a living body.
Among all, there has been no polyethylene glycol having an average molecular weight of from 190 to 210 which meets the requirement for ethylene glycol and diethylene glycol content as defined in United States Pharmacopoeia and the Pharmacopoeia of Japan, i.e., 0.25% (2,500 ppm) or less [J P Forum; Vol. 8, No. 4, 291-297 (1999)]. Although some polyethylene glycol products having an average molecular weight of 211 to 420 meet this standard, there is a requirement in fields concerning the living body such as the drug and cosmetic fields to further lessen the ethylene glycol and diethylene glycol contents.
With respect to polyethylene glycol having an average molecular weight of from 421 to 1,050, even commercial products meet the standards of the ethylene glycol and diethylene glycol contents stated in the United States Pharmacopoeia, i.e., 0.25% (2,500 ppm) or less. In fields concerning the living body such as the drug and cosmetic fields, however, there is a requirement to further lessen the ethylene glycol and diethylene glycol contents.
It has been a common practice to produce polyethylene glycol by addition-polymerizing ethylene oxide to ethylene glycol or diethylene glycol in the presence of an alkali catalyst such as sodium hydroxide or potassium hydroxide with heating under elevated pressure. In this process, the remaining ethylene glycol or diethylene glycol decreases with an increase in the average molecular weight of the polyethylene glycol. In the case of polyethylene glycol having a relatively low molecular weight of from 190 to 420, the starting ethylene glycol or diethylene glycol tends to remain in large amounts.
In the case of polyethylene glycol having an average molecular weight of from 421 to 1,050, the ethylene glycol or diethylene glycol remains in a small amount compared with polyethylene glycol having an average molecular weight of from 190 to 420. However, ethylene glycol or diethylene glycol still remains in an amount exceeding the level required in the market.
Since these materials contain water, ethylene oxide is addition-polymerized with water so as to form ethylene glycol and diethylene glycol.
To remove ethylene glycol and diethylene glycol remaining in polyethylene glycol, use may be made of a method wherein low-boiling ethylene glycol and diethylene glycol are removed while bubbling nitrogen at a high temperature under reduced pressure. However, this method suffers from a problem in that when the contents of ethylene glycol and diethylene glycol are reduced to the level indicated by the following formula [I], the yield is largely lowered and deterioration arises due to excessive heating.                               Sum          ⁢                      xe2x80x83                    ⁢          of          ⁢                      xe2x80x83                    ⁢          ethylene          ⁢                      xe2x80x83                    ⁢          glycol          ⁢                      xe2x80x83                    ⁢          and          ⁢                      xe2x80x83                    ⁢          diethylene          ⁢                      xe2x80x83                    ⁢          glycol          ⁢                      xe2x80x83                    ⁢          contents          ⁢                      xe2x80x83                    ⁢                      (            ppm            )                          =                              150            xc3x97            2900            xc3x97                          0.85                                                (                                      x                    -                    150                                    )                                /                44                                              x                                    [        I        ]            
wherein x represents the average molecular weight of the polyethylene glycol.
Accordingly, an object of the present invention is to provide a polyethylene glycol having an average molecular weight of from 190 to 1,050 for use in fields with application to a living body, wherein the sum of the contents of ethylene glycol and diethylene glycol is extremely low, and a process for producing the same.
The above object of the present invention has been achieved by providing:
(1) polyethylene glycol for use in fields with application to a living body, wherein the sum of the contents of ethylene glycol and diethylene glycol in the polyethylene glycol is less than or equal to that expressed by the following formula [I]:                               Sum          ⁢                      xe2x80x83                    ⁢          of          ⁢                      xe2x80x83                    ⁢          ethylene          ⁢                      xe2x80x83                    ⁢          glycol          ⁢                      xe2x80x83                    ⁢          and          ⁢                      xe2x80x83                    ⁢          diethylene          ⁢                      xe2x80x83                    ⁢          glycol          ⁢                      xe2x80x83                    ⁢          contents          ⁢                      xe2x80x83                    ⁢                      (            ppm            )                          =                              150            xc3x97            2900            xc3x97                          0.85                                                (                                      x                    -                    150                                    )                                /                44                                              x                                    [        I        ]            
wherein x represents the average molecular weight of the polyethylene glycol and the polyethylene glycol has an average molecular weight ranging from 190 to 1,050; and
(2) polyethylene glycol having an average molecular weight of from 190 to 210 for use in fields with application to a living body, containing ethylene glycol and diethylene glycol in a total amount of 200 ppm or less.
The formula [I] above is a formula whereby the sum of the ethylene glycol and diethylene glycol contents in polyethylene glycol at each molecular weight is calculated.
The ethylene glycol and diethylene glycol contents at each molecular weight are appropriately selected depending on the requirements of an intended application. In case of use in fields with application to a living body, it is favorable from the viewpoint of toxicity that the sum of the ethylene glycol and diethylene glycol contents is 2,500 ppm or less at a molecular weight of 200. Since the sum of ethylene glycol and diethylene glycol contained in the material and the sum of ethylene glycol and diethylene glycol formed as by-products during the reaction decrease with an increase in the addition mole number of ethylene oxide, the sum of the ethylene glycol and diethylene glycol contents in the product amounts to a value calculated by multiplying by a definite decreasing ratio.
In the above formula, 150 represents the molecular weight of triethylene glycol and 2,900 represents a coefficient concerning the acceptable level of the ethylene glycol and diethylene glycol contents in the material.
(x-150)/44 means the addition mole number of ethylene oxide. In the case where the decreasing ratio of the sum of the ethylene glycol and diethylene glycol contents per mole of ethylene oxide added is referred to as 0.85, the upper limit of the sum of ethylene glycol and diethylene glycol contained per mole (x g) of polyethylene glycol is thus indicated.
For some purposes, yet lower ethylene glycol and diethylene glycol levels are required. In the case of polyethylene glycol having a low molecular weight of from 190 to 210, in particular, the sum of the ethylene glycol and diethylene glycol contents is desirably 200 ppm or less.
The present invention further provides a process for producing such a polyethylene glycol. More particularly, the present invention provides:
(3) a process for producing polyethylene glycol according to (1) or (2) above which comprises addition-polymerizing ethylene oxide to triethylene glycol; and
(4) the process for producing a polyethylene glycol according to (3) above, which comprises, before the addition polymerization with ethylene oxide, dehydrating the triethylene glycol in a reactor at 70 to 150xc2x0 C. under a reduced pressure of from 0 to 0.013 MPa for 0.5 to 3 hours.
The polyethylene glycol provided by the present invention is a polyethylene glycol for use in fields with application to a living body which has an average molecular weight ranging from 190 to 1,050, and the sum of the contents of ethylene glycol and diethylene glycol is less or equal to that expressed by formula [I] below.
The polyethylene glycol provided by the present invention, which is a polyethylene glycol having an average molecular weight ranging from 190 to 210 and the sum of the contents of ethylene glycol and diethylene glycol of less than or equal to that expressed by the following formula [I], still preferably 200 ppm or less, is highly useful. This is because there has been no polyethylene glycol meeting the standards as defined in the Pharmacopoeia of Japan and United States Pharmacopoeia and such a polyethylene glycol is in high demand in the market.                               Sum          ⁢                      xe2x80x83                    ⁢          of          ⁢                      xe2x80x83                    ⁢          ethylene          ⁢                      xe2x80x83                    ⁢          glycol          ⁢                      xe2x80x83                    ⁢          and          ⁢                      xe2x80x83                    ⁢          diethylene          ⁢                      xe2x80x83                    ⁢          glycol          ⁢                      xe2x80x83                    ⁢          contents          ⁢                      xe2x80x83                    ⁢                      (            ppm            )                          =                              150            xc3x97            2900            xc3x97                          0.85                                                (                                      x                    -                    150                                    )                                /                44                                              x                                    [        I        ]            
wherein x represents the average molecular weight of the polyethylene glycol measured by the method described in the xe2x80x9cPolyethylene glycol/Official Monographsxe2x80x9d section of THE UNITED STATES PHARMACOPEIA 24, THE NATIONAL FORMULARY 19, published by UNITED STATES PHARMACOPEIAL CONVENTION, INC. on Jan. 1, 2000.
The upper limits at respective molecular weights calculated in accordance with the above formula [I] are as follows: 1,808 ppm in case of a polyethylene glycol having a molecular weight of 200, 833 ppm in case of a polyethylene glycol having a molecular weight of 300, 432 ppm in case of a polyethylene glycol having a molecular weight of 400, 138 ppm in case of a polyethylene glycol having a molecular weight of 600, and 19 ppm in case of a polyethylene glycol having a molecular weight of 1,000.
Preferred values at respective molecular weights are as follows: 200 ppm in case of a polyethylene glycol having a molecular weight of 200, 150 ppm in case of a polyethylene glycol having a molecular weight of 300, 100 ppm in case of a polyethylene glycol having a molecular weight of 400, 50 ppm in case of a polyethylene glycol having a molecular weight of 600, and 15 ppm in case of a polyethylene glycol having a molecular weight of 1,000.
A polyethylene glycol having the sum of ethylene glycol and diethylene glycol contents exceeding the level as defined by the above formula [I] is undesirable because of the excessively high content of impurities. The lower limit of the sum of ethylene glycol and diethylene glycol contents may be 1 ppm or more in view of the detection limit of the measurement method.
The polyethylene glycol for use in fields with application to a living body provided by the present invention is a physiologically useful polyethylene glycol. More particularly, it is a polyethylene glycol which is usable in products directly applied to the human body in fields with application to a living body such as drugs, cosmetics and toiletries. For example, it is useful as a medicinal base in dissolution aids, emulsifiers, dispersants, fillers, lubricating agents, etc., for injection preparations, external preparations, oral preparations and the like. Furthermore, it is useful as a cosmetic material for body cleansers such as toilet soaps, shampoos, rinses, facial cleansers and toothpastes and cosmetics such as cosmetic lotions, lotions, foundations, perfumes and lipsticks.
The polyethylene glycol provided by the present invention which has small ethylene glycol and diethylene glycol contents and an average molecular weight ranging from 190 to 1,050 can be produced by addition-polymerizing ethylene oxide to triethylene glycol in the presence of an alkali catalyst such as sodium hydroxide or potassium hydroxide.
Although the triethylene glycol for use as a starting material is not restricted in purity, it is preferable to use triethylene glycol having a purity of 99.5% or more, still preferably 99.95% or more. The triethylene glycol purity can be elevated by distilling, etc.
The alkali catalyst for use in the present invention is a strongly alkaline substance such as sodium hydroxide or potassium hydroxide. It is preferably added in an amount of from 0.005 to 1.0% by weight, still preferably from about 0.01 to 0.5% by weight, based on the triethylene glycol that is supplied.
In the production process provided by the present invention, the ethylene oxide addition-polymerization reaction is carried out preferably at a reaction temperature of from 80 to 230xc2x0 C., still preferably from 120 to 180xc2x0 C., and under a reaction pressure of from 0 to 1 MPa, still preferably from 0.2 to 0.6 MPa.
The formation of ethylene glycol and diethylene glycol as by-products can be suppressed, prior to the addition-polymerization of ethylene oxide to triethylene glycol, by heating triethylene glycol in a reactor to 70 to 150xc2x0 C. and bubbling nitrogen gas under reduced pressure of 0 to 0.013 MPa for 0.5 to 3 hours to thereby eliminate water from the starting materials and the catalyst.
In this case, the ethylene glycol and diethylene glycol contents can be determined by the following method.
This method is carried out by reference to Echiren Gurikoru Oyobi Jiechiren Grikoru no Gendo (Limit of Ethylene Glycol and Diethylene Glycol) described in Poriechiren Gurikoru no Kokusai Chowa An (International Harmonization Proposal of Polyethylene glycol) (Stage 3), J P Forum,; Vol. 8, No. 4, 291-297 (1999). The determination conditions are as follows.
 less than Conditions for the Determination of Ethylene Glycol and Diethylene Glycol Contents greater than 
Preparation of internal standard solution: 100 mg of 1,4-butanediol is precisely weighed in a 100 mL graduated flask and diluted up to the marked line with distilled water.
Preparation of standard solutions: 50 mg portions of ethylene glycol, diethylene glycol and 1,4-butanediol are each precisely weighed into a 100 mL graduated flask and diluted with distilled water.
Preparation of sample solutions: 4 g portions of samples to be measured are each precisely weighed into a 10 ml container and 5 ml of the internal standard solution and 1 ml of distilled water are precisely added thereto. After capping, the mixture is well shaken.
Analytical conditions: Gas chromatographic measurement is carried out under the following conditions.
Column: WCOT FUSEDSILICA 30 mmxc3x970.53 mm CP WAX 52CB film thickness: 1.0 xcexcm (manufactured by GL Science).
Carrier gas: He (helium gas).
Linear velocity: 40 cm/sec.
Split vent flow: 100 ml/min.
Injection temperature: 250xc2x0 C.
Detector temperature: 260xc2x0 C.
Column temperature: 180xc2x0 C.xe2x86x9210xc2x0 C./minxe2x86x92260xc2x0 C. (22 min).
Injection volume: 1 xcexcl.
Calculation method: A response coefficient FN is calculated based on the peak areas obtained from the standard solution and each sample solution with the use of formula (1) below. Then, ethylene glycol and diethylene glycol are quantified using the formula (2).
FN=(CNrSI)/(CSIrSN)xe2x80x83xe2x80x83(1)
CN: concentration (xcexcg/ml) of ethylene glycol or diethylene glycol in the standard solution
rSI: peak area of the internal standard obtained from the standard solution;
CSI: concentration (xcexcg/ml) of the internal standard in the standard solution; and
rSN: peak area of ethylene glycol or diethylene glycol obtained from the standard solution.
Content (% by weight)=(FNCIrN)/(2000rIW)xe2x80x83xe2x80x83(2)
CI: concentration (xcexcg/ml) of the internal standard in the internal standard solution;
rN, rI: peak areas of ethylene glycol or diethylene glycol and the internal standard obtained respectively from the sample solutions;
W: weight (g) of each target substance in the sample solution.
Content (ppm)=content (% by weight)xc3x9710000 xe2x80x83xe2x80x83(3)
The polyethylene glycol obtained by the present invention can be further processed by eliminating excessive ethylene oxide under reduced pressure and by eliminating the alkali catalyst by neutralizing the alkali catalyst with an acid such as phosphoric acid or hydrochloric acid or using an adsorbent. Furthermore, antioxidants such as dibutylhydroxyltoluene and tocopherol may be added thereto depending on the intended purpose.
Now, the invention will be illustrated in greater detail by reference to the following Examples. However, the present invention should not be construed as being limited thereto.